Research Interests

One of the enduring goals of the Miami Project has been to test and implement treatment strategies that optimize the long term health of persons with SCI. One strategy employed to attain this goal has been to investigate physical activity as a means of preventing medical complications that arise from physical deconditioning. In past years these studies have examined how electrically-stimulated cycling and ambulation exercise affect fitness levels in persons with tetraplegia and paraplegia. The findings of these studies support our belief that physical activity can improve fitness, heart function, and peripheral circulation, and that exercise training programs benefit the structure and function of muscle. Both direct and indirect evidence obtained from these studies suggests that exercise lowers physical and emotional stress by reducing the release of stress hormones from the adrenal glands, or altering the way in which target tissues respond to stress challenges.

There is widespread concern that the population of persons who survive SCI is aging, and that the passing of time presents an entirely new set of physical and health challenges for those who were injured years ago. We have anticipated these changes and targeted some of our research to address the effects of exercise on the functions of the heart and circulation for those who are older than 40 years. This research has also examined the naturally-occurring decline in shoulder joint function that accompanies aging with SCI as well as the disposition to heart and circulatory diseases. Results of these trials have been very encouraging, and confirm that exercise interventions are successful in reversing longstanding deconditioning and muscle weakness. Subjects involved in these trials have also benefitted by improved cardiac function at rest and during activity, and through blood lipid changes that slow the natural course of heart disease. As in our previously published findings, this work holds great promise for improving health and function while reducing disease susceptibility for those who live with SCI.

MARC: Give us the early background on Mark Nash, where you grew up, all that background, how’d you get to The Miami Project?

DR. NASH: I was born and raised outside Cleveland. I did my undergraduate work at The University of Toledo with a triple undergraduate major in Biology, Chemistry and Philosophy. I then received a Masters degree in Molecular Genetics and Human Biochemistry. And then my Ph.D. was both in the Medical College of Ohio and the University of Toledo (they have since merged) in Applied Physiology and Clinical Anatomy. My focus was really rehabilitation of people with heart disease.

MARC: Was that your dissertation?

MN: My dissertation was a study that examined exercise in diabetic mice, especially looking at kidney (glomerular) disease. Otherwise, all of my clinical work was directed toward going in to a professional career in rehabilitation of ischemic heart disease. I worked with a very skilled surgeon in the Midwest – who shares a lot of professional attributes with Dr. Green. We had worked about a year to design the rehabilitation program for his patients at an academic medical center in Northeast Ohio. That was actually the plan.

MARC: So when you went into your undergraduate work you were undecided and not yet interested in medicine?

MN: I was still undecided. I liked medicine, but I wasn’t sure that seeing patients all day long was what I wanted to do. I really liked the idea of research and always had a natural curiosity about me.

MARC: What flicked a switch to say ‘you know what, I’m going into research and deciding to get your Master’s and Ph.D.?

MN: I had spoken to a number of physicians and colleagues who weren’t happy just doing clinical work, and a lot of them had expressed an interest in contributing more to their respective fields, to direct treatments, and to see what they were doing was more evidence- based. I thought it made a great deal of sense to do the studies, find out what is and is not evidence-based, and to translate that into patient care. All of this was very attractive to me.

MARC: Was there one professor that inspired you or a class that you took that inspired you?

MN: I had a wonderful Ph.D. advisor, Fred Andres, who was very skilled both in clinic and in research. We had an excellent relationship and I really enjoyed working with him. I did my last year as a Doctoral Fellow working with 2 people. The first was Dr. Larry Durstine, who is now Distinguished Chair of Exercise Science at the University of South Carolina-Columbia and past President of the American College of Sports Medicine. The other was Dr. Tom Burke, who was then Director of the Cardiac Rehabilitation Program at Riverside Hospital in Toledo. Dr. Burke is currently a Dean at Wayne State University and has since published some work in cardiovascular regulation after SCI. Thus, we talk from time to time and I bounce new research ideas off of him.

MARC: All of this work still in cardiac?

MN: Absolutely – to this point I had never heard of spinal cord injury or even met anyone in a wheelchair, a little fact that was fortunately overlooked by Dr. Green when he interviewed me.

MARC: Alright, so what happened? How did you make that corner?

MN: Well, my mentor in June/July 1984 came into the lab one day and said he had been at a meeting where a speaker had talked about injuries to the spinal cord from diving accidents. The speaker was Dr. Barth Green. Afterwards they went out to dinner and it seemed that Barth was looking for a new Director for the Functional Electrical Stimulation Research Program he had started in Neurological Surgery and apparently looked at my mentor and said ‘do you know any physiologists who are looking for a job’? My mentor said, ‘…well, my Fellow is coming out in a couple of months’ and Barth asked about me. A week later I received a call saying ‘I’m calling on behalf of Dr. Green, we’d like to invite you to Miami.’

MARC: Had you ever been to Miami before?

MN: Once when I was a kid. But I actually wasn’t the slightest bit interested in coming down here. My mentor actually had to say, “Mark, they’ll pay for you to go to Miami” so I said ok, I’ll go. So, I flew in and Dr. John Klose picked me up at the airport on a Sunday night, took me to the hotel across the street, and after I spent a few days here, Dr. Green offered the position. I thought this was very unusual for a number of reasons. First, I had absolutely no training in Spinal Cord Injury. Second, I was offered the position of Director of Functional Electrical Stimulation Program and I have absolutely no training in Electrical Stimulation. Third, I was supposed to be the ‘Director’ but I really had no training in Administration. Nonetheless, this is what Dr. Green had offered, and had never asked me if I had actually ever met anyone in a wheelchair. In my opinion I was totally unqualified for the position, but I thought it was interesting, different, and challenging. It was totally different from where I was going professionally, and I thought the people with whom I was working would probably be needing me more than the people with ischemic heart disease who had lots of options to take care of themselves. At that time people with spinal cord injuries certainly had fewer exercise options, and we saw the electrical stimulation cycling for the first time and it was wide open for research. There truly was nothing that had been done, so basically it was a blank sheet of paper for us.

I recall asking Dr. Green for a position description and he simply replied ‘you’re the Director’ and I said ‘well, what should I be directing?’ and he said ‘you should direct everything that needs directing’ and I said ‘well, how will I know what that is?’ and he said ‘you’ll probably need to ask the Director’. End of discussion – almost. He continued with ‘I want you to have a research program’ and I said ‘what should I be researching?’ and he said ‘you should research everything that needs to be researched’ and I said ‘if I don’t know what to do?’ and he said ‘go talk to the Director’. That was the job description.

MARC: So, he left you with no road map?

MN: I saw it as a great opportunity to make the program what I wanted, and I think that was the uniqueness of what was here. We certainly didn’t know much about electrical stimulation, we didn’t know much about exercising people with spinal cord injury - very little had been studied - and therefore you could kind of make your own turf. This contrasted the field of cardiac rehabilitation where there were well established protocols, the systems were all in place, and it was kind of ‘plug and play’. That’s one of the things that made it so attractive.

MARC: Tell me about your first year. What kind of learning curve did you face?

MN: It was hard. There was really no one to talk to, as there were very few people who had done anything similar. At the time I didn’t fully understand the physiology of spinal cord injury because I hadn’t trained in the area. For example, I didn’t know what autonomic dysreflexia was the first time it happened. The first time we put electrical current into one of our research subjects his blood pressure went over 300. Fortunately Barth was across the hall and I had him come over and asked ‘what on earth is happening?’ He told me ‘oh that’s autonomic dysreflexia’. I queried why his pressure was so high and the heart rate so low’ and Dr. Green just said ‘think about it for a minute’ and I did. It made some sense if you figured it out, but there was an awful lot that I didn’t know. I was fortunate because the first thing I did was follow Barth around for the first six months. I did every patient I could with him - every Wednesday - and I was in the OR with him every opportunity I could possibly get. It was an education you don’t get out of the textbook and I think it was one of the extraordinary experiences of my career was to follow him around and talk about patients. I was also very fortunate there were people like Kathy Klerk, Robin Smith, and Janie Escobar at Jackson Memorial Rehab, who were very forthcoming with information when I had a lot of questions The staff in neurosurgery and orthopedics were also very helpful. But it was still a tough year.

MARC: So what was the first thing that you studied? Was this the functional electric stimulation (FES) Regys bike?

MN: The study that took place involved the large electrical stimulation cycle and it involved us, Wright State University, Mt. Sinai Medical Center of New York, and Craig Rehabilitation Hospital in Denver. Mostly, we were looking at safety, tolerance and effectiveness. The effectiveness outcomes weren’t very sophisticated and we primarily wanted to see whether lower limb muscle became larger after treatment..

MARC: So the variable was muscle mass?

MN: At that time it was really muscle mass we studied more than anything. And safety, of course.

MARC: It wasn’t cardiovascular? That came later?

MN: We had examined some heart rate responses, but they’re so unusual that it really wasn’t fruitful to look at them. Looking back 26 years, if I knew what I know now, I would have been looking at lipid levels and different aspects of cardiac function. The approach probably would have been a whole lot different.

MARC: Starting with FES, your research has expanded well beyond that. If you were to give me the highlights of your research career in the last 25 years, how would you sum up maybe the top 3 things that you’ve been able to research?

MN: I think we’ve confirmed that there’s a benefit to using exercise conditioning using electrical stimulation, and I think that was important to us and our colleagues.

MARC: Fair to say that you and a handful of other people pioneered FES research in spinal cord injury?

MN: I think if we didn’t pioneer the process, we pioneered how the application would be used to the benefit of people with SCI.

MARC: Let me just back up, when you say benefitting, not just muscle mass, but what have we shown? What have we demonstrated?

MN: Circulatory function, lipid benefits, reduction in cardiovascular disease risks. I still have patients like Ricky Palermo who started with me in 1985/1986 and is still riding the cycle 3 days a week. So there are a lot of the patients from the very beginning who are still out there. There’s actually one in Puerto Rico who we still program a cartridge for, so some of the original research subjects and patients still stay in contact are doing the exercise regularly.

Speaking of Ricky, I was up in Rochester recently and I presented a grand rounds session at University of Rochester Medical Center. Afterwards I presented a consumer talk at Strong Memorial and we were talking about our clinical trial at a luncheon. There were probably 50 or 60 consumers with family members. It was really a nice session; I never actually got to talk about rehab, just the clinical aspects of ongoing and future SCI trials. We talked about exactly where we were, where we’re going, and why has it taken so long. I explained the steps we still have to take, the barriers needed to be overcome, and how we’re approaching them.

MARC: Would you say the reason that we no longer do traditional FES like we had before is that we pretty much exhausted the research on that end and have proven what we’ve proved and it’s time to move on to bigger and better things?

MN: I think there were a number of reasons, and that’s one of them. The second issue is that the Miami Project is a research center and we don’t support fee-for-service programs as they did in Neurological Surgery. So when Richard and Mary Bunge arrived in 1989, there was a much greater focus on research. Our clinical research moved to the Bantle Center in September of 1989, the focus on research was going to be much more extensive, and time available to conduct the research at a premium. The FES treatment is also very time and labor intensive. The third reason is that funding for the FES cycling studies was very difficult to come by, as there was only one manufacturer of the FES unit. If there’s only one manufacturer that means that one company makes all of the money, and that’s not the best scenario to obtain Federal funding.

MARC: Now there are a handful of companies

MN: Well now there are 2 or 3 that manufacture the unit. However, from my point of view we wanted to validate the process and show that it was safe. After we did that, there were other research frontiers to pursue.

MARC: Alright so we researched that piece of equipment

MN: Well the second of the frontiers was voluntary exercise and to get away from the arm crank machine. There was some evidence that arm cranking probably wasn’t the best for the shoulders, and it was boring to the person doing it. When we moved down to the Bantle Center one of the first things we did was to start moving back to resistance models, doing more of the circuit models that we still use today, and they proved to be much more effective than arm cranking for many of the needed attributes of fitness. So we combined resistance models and the circuit models and it lead to 3 or 4 Federal grants.

MARC: Can you give me an example?

MN: Sure. We’ve now moved beyond just the physical attributes of strength, anaerobic power and aerobic endurance into examining cardiovascular benefits. At present we’re examining blood vessel walls at the molecular level, and trying to find out what’s actually happening in the blood vessel wall when it’s training and in-between training sessions. Examining gene expression of cardiovascular disease isn’t that far off.

MARC: So instead of training with the arm crank, how are they training?

MN: We’re using weight lifting, resistance equipment. We can do that with equipment we have downstairs, which is large and expensive. Or, we can do it at centers that have actually replicated our model with smaller equipment.. In 1992 some of my graduate students validated the model with Thera-band. They went out and bought some inexpensive elastic bands, got very creative with it, and designed a home-based exercise program. As I only gave them $50 to buy all of the components it actually became an interesting option for people with SCI who don’t have a lot of money to spend but want to keep themselves fit. Alan Troop has written a funny story about it, and that it works. Another area in which we’re addressing early cardiovascular disease involves drug studies that we’ve now completed and are also expanding. We completed the first study that looked at Niaspan; and presented the paper at the American Spinal Injury Association meeting this past year, Currently we’re funded by the Craig Nielsen Foundation to test whether a simple aspirin-like drug can treat impaired fasting glucose and vascular inflammation accompanying high fat food intake.
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MARC: So that’s now an accepted protocol for people?

MN: We now have exercise and drug protocols for treating lipid disorders in the population. These interventions are an important step toward people with SCI living longer - and if not longer, we expect them to live better. And I think a part of that attitude has also changed. The old notion of a living a sedentary lifestyle verses leading an active, satisfied, productive, independent life with paralysis has changed profoundly in 25 years.

MARC: Do you have any other high points?

MN: I think those are the 3 key areas. We validated these studies, created new models and now we’re actually down at the molecular level examining how to stop vascular damage with the intent of stopping the damage that leads to cardiovascular medical complications.

MARC: At some point whether it’s soon or later, there will be a functional recovery to paralysis I believe. I believe that in my heart. It might not be next year when we do our transplant, who knows when but at some point, there will be enough good research to reconnect the cord and get functional and sensational function back at some level. Therapy will definitely play a role, how do you feel and envision it playing a role? Do you think it will be like people having to learn how to crawl, walk and really retraining the body? I know I’m kind of asking you a question about something that hasn’t been discovered yet.

MN: We’ve actually thought a lot about it.

MARC: Tell me about, how do you think, if this trial goes well, and we actually see some recovery what kind of therapy will we be working on to help?

MN: Well, I think that the first thing is that we will need to be doing a lot more therapy before people undergo these procedures. A lot of it will involve pre-conditioning for those who have, over the years, not engaged in these activities. It may be without that pre-training, even functional restoration of the nervous system may not be sufficient to make a weakened musculoskeletal system functional. So I see challenges in directing the training more specific types of activities rather than general fitness.

MARC: So pre-training, getting people up to par before the transplant will be key.

MN: Right, again as a practical matter. We’ve said to people for years that NASA didn’t pick weak, de-conditioned people to go to the moon. They picked people who could overcome the challenges imposed by the environment. I think we’re going to have to do the same thing, take people who are capable of benefitting from the process as quickly as possible.

MARC: So then, I want to make sure I get it right. You would say that it is going to be very structured on the pre-training side, people will go through a very structured exercise program, but after, it is going to also be very specialized?MN: Exactly. We have to find what is and isn’t working, and determine why with assessments using the tools we have. EMG, cortical stimulation, MRI, and electrical stimulation will all become very important, as will the knowledge and experiences of our colleagues who routinely use them.

MN: Exactly. We need to keep people motivated, we need to keep people focused on possibilities and the fact that this has been a long term process. You’ve done 25 years in the chair, that’s a lot of deterioration, that’s a lot of de-conditioning, we need to get it back. There are some systems of the body that better lend themselves to reconditioning than others, so we have to be cautious not to overwork those that are more susceptible to injury. Conversely, cardiac muscle, skeletal muscle and other tissues respond enthusiastically to reconditioning after years of disuse. Bone is not very forgiving, so we need to better understand how to preserve it and restore it. We also need to know more about drug approaches with physical activity and other modalities; perhaps vibration, perhaps electrical current, and perhaps some new drugs that are being used to treat osteoporosis.

MARC: You’ve seen a lot over 25 years, I thought it was one of Richard Bunge’s classic lines, he said ‘I’ve seen the ignorance crumble’ What about you?

MN: It’s very exciting to think of what we dreamed about a quarter century ago is coming to fruition now. The irony for me is when Dr. Green interviewed me, he described this scenario even before it existed. We took a drive out on Key Biscayne to show me the sights, and I ask him ‘what would you like to do with the rest of your career’? He said he’d want to cure paralysis’ and I remember commenting (something like) ‘kind of a lofty aspiration, don’t you think?’ - and I was glib about it. So Barth pulled the car over on the Rickenbacker Causeway where we sat there for an hour and he described what we would need to accomplish the goal. We need dedicated people, we need enough money so that we’re not fully reliant on federal sources, we need a center of excellence that is dedicated to this problem and nothing else, and the scientists need the time in the course of the day to do our work. Barth felt this could be done, and actually described this place in remarkable detail 25 years ago. So it’s enjoyable for me to see this dream come to fruition. In 1984 I started in my 1st lab, which was about the size of your current office. To now work in a state-of-the-art research building and appreciate the size and the scope of our activities is more than dramatic. Back then I knew what everybody was doing in their research labs and now that’s not possible – at least in any kind of detail. This speaks well for where we’ve come. And back then not everyone liked the words “to cure paralysis” on the back of our name as it was thought to be too forward and offer hope that would never come to fruition. 25 years later we have a lot to show for this effort as we approach clinical trial, and as for curing paralysis, it’s one day closer than if we started one day later. And I find that very exciting.